Autoimmune diseases are diseases arising from aberrant response of the immune system against one's own substances and tissues. There are more than 80 different types of autoimmune diseases that, collectively, amount to the number two cause of chronic illness, and one of the top 10 leading causes of death in women of all age groups up to 64 years.
Significant medical research efforts have been devoted to understanding the mechanism of autoimmune diseases and finding effective diagnosis and treatments therefore. Many autoimmune diseases are now characterized by the presence and undesirable activities of autoantibodies. These autoantibodies recognize and bind to often normal and healthy self antigens, thereby causing significant damages and failures of relevant tissues and organs.
Many autoimmune antigens have been identified by immunoassays with sera from patients with autoimmune diseases. One of such target antigens is moesin—membrane-organizing extension spike protein, found to be reactive to autoantibodies in patients with rheumatoid arthritis (RA). Wagatsuma et al., Mol. Immuol., 33:1171-6 (1996). Moesin was initially identified in bovine uterus and characterized as a possible receptor for heparin. Lankes et al., Biochem J. 251:831-42 (1988). Further studies have characterized moesin as a member of the ezrin-radixin-moesin (ERM) protein family. These are proteins that are primarily expressed in cytoplasm, concentrated in actin rich cell-surface structures. They act as structural linkers between the plasma membrane and the actin cytoskeleton, playing roles in the formation of microvilli, cell-cell adhesion, maintenance of cell shape, cell mobility and membrane trafficking. Later studies have revealed that they are also involved in physiological and pathological signal transductions. Louvet-Vallee, Biol. Cell 92:305-16 (2000).
Sequence and structural analysis of the ERM proteins revealed that they share high degrees of inter-species and inter-molecular homologies. The ERM proteins have three domains: an N-terminal domain called FERM domain (band four-point-one, ezrin, radixin, moesin homology domain) because of its homology with the band 4.1 protein, a central helical domain and a C-terminal tail domain. The C-terminal tail domain binds F-actin while the N-terminal FERM domain is responsible for binding to adhesion molecules in the plasma membrane. Louvet-Vallee (2000).
Wagatsuma et al (1996) reported detections of anti-ERM autoantibodies in RA patients. Of the 71 patient sera tested, 24 samples (33.8%) reacted with at least one of the recombinant ERM antigens and 10 samples (14%) reacted with recombinant moesin alone. However, the study did not find significant correlation between the presence of anti-ERM antibodies and clinical manifestation, such as disease duration or stage. Moreover, sera from patients with other autoimmune diseases such as Primary Sojgren's Syndrome (PSS) and systemic lupus erythematosus (SLE) did not show any reactivity to the three ERM proteins.
Takamatsu et al reported detection of specific antibodies to moesin in the sera of patients with acquired aplastic anemia (AA). Takamatsu et al., Blood 109:2514-20 (2007). Using ELISA, anti-moesin antibodies were shown at high titers in 25 of 67 (37%) AA patients. Further in vitro studies showed that anti-moesin antibodies from AA patients induced inflammatory cytokines such as TNF-α and IFN-γ, implicating its role in the pathophysiology of the disease. Espinoza et al., Intl. Immu. 21:913-23 (2009); Takamatsu et al., J. Immunol. 182:703 (2009).
One of the challenges in clinical management of autoimmune diseases is the accurate and early identification of the diseases in a patient. To this end, it would be highly advantageous to have molecular-based diagnostic tools that can be used to objectively identify presence and/or extent of disease in a patient. The present application described herein provides these tools and other benefits.